#SUO14 - Session Highlights: Non-genomic AR pathway

December 5, 2014

BETHESDA, MD USA (UroToday.com) - Jeremy Jones from the City of Hope presented work on non-canonical AR signaling. AR is best known as a transcription factor which is translocated to the nucleus to activate androgen-dependent transcription programmes.
This pathway takes several hours to occur. However, data from as early as 1999 showed that kinase cascades are activated within minutes after stimulation with dihydrotestosterone (DHT). Additionally, the actin cytoskeleton and calcium signaling are also altered on a much faster time-scale. Many of these nongenomic actions can contribute to anti-androgen resistance. Additionally, some of these non-genomic signals can actually decrease cell migration and induce apoptosis. Several independent groups have described binding sites for androgens in cells without AR. For example, albumin-conjugated androgen cannot penetrate the membrane, but localizes to the membranes of cells, and this localization is not blocked by competitive antagonists. In 2010 the nutrient-sensing G-protein coupled receptor GPRC6a was shown to mediate non-genomic effects of androgens. Activation requires higher concentrations of androgens and induces rapid non-genomic signaling. Gprc6a-null mice exhibit osteopenia, feminization, and metabolic syndrome. Crossing Gprc6a knockout mice to the TRAMP genetically engineered prostate cancer mice slowed prostate cancer development. In a second study from this year, the zinc transporter ZIP9 was also found to be an AR-independent androgen receptor. ZIP9 is a 7-transmembrane receptor that has a lower affinity to testosterone (like GPRC6a) as well as other steroids. It behaves as a tumor suppressor by induction of apoptosis upon activation.

Dr. Jones summarized by saying there is still much to learn, but suggested that the key question to answer is how to distinctly engage GPRC6a and ZIP9 oncogenic and tumor suppressing signals distinctly with non-androgen ligands. He closed by alluding to the RESTORE trial which will evauluate supraphysiologic testosterone dosing upon progression after abirateribe/enzalutamide. He hypothesized that effects seen with this treatment algorithm may actually be mediated through these two non-AR receptors.

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